Is PDHA1 p.Arg263Pro (c.788G>C) pathogenic?

PDHA1 p.Arg263Pro (c.788G>C) is classified Conflicting classifications of pathogenicity in PDHA1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-04-22). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PDHA1 p.Arg263Pro (c.788G>C)?

PDHA1 p.Arg263Pro (c.788G>C) is associated with Inborn genetic diseases, pyruvate dehydrogenase E1-alpha deficiency (ClinVar).

How common is PDHA1 p.Arg263Pro (c.788G>C) in the general population?

PDHA1 p.Arg263Pro (c.788G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PDHA1 p.Arg263Pro (c.788G>C)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

PDHA1 p.Arg263Pro

c.788G>C · rs2063192428 · VCV1184474

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic · top 7% in PDHA1
REVEL	0.983	strongly pathogenic-leaning
SaProt	LLR -18.12	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 2,237 bp · p 0.011 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PDHA1
Protein: p.Arg263Pro
Coding: c.788G>C
MANE Select: NM_000284
dbSNP: rs2063192428
Type: single nucleotide variant
Location: chrX:19355714 (GRCh38)
Structure: AlphaFold pLDDT 94.77 · 9 PDB
Residue 263: an α-helix; a UniProt-annotated variant site (in pdhad)

Full PDHA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pyruvate dehydrogenase E1-alpha deficiency

Similar variants

PDHA1 p.Arg263Gly Pathogenic ★★ same residue
PDHA1 p.Arg263Ter Pathogenic ★★ same residue
PDHA1 p.Arg263Gln Pathogenic ★ same residue
PDHA1 p.Arg263Leu Likely pathogenic ★ same residue
PDHA1 p.Ala169Val Pathogenic ★★★ same condition
PDHA1 p.Arg304Ter Pathogenic ★★★ same condition
PDHA1 p.Arg378Cys Pathogenic ★★★ ⚠ same condition
PDHA1 p.Arg72Cys Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pdha1-p-arg263pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown